AKT collaborates with ERG and Gata1s to dysregulate megakaryopoiesis and promote AMKL.

Abstract:

:The requirement that leukemic Gata1 mutations be present in cells harboring trisomy 21 led to the discovery that overexpression of ERG drives aberrant megakaryopoiesis. Given that constitutive PI3K/AKT signaling is a frequent component of hematologic malignancies and the relationship between AKT and Notch in this lineage, we studied the crosstalk between AKT signaling and ERG in megakaryopoiesis. We discovered that constitutive AKT signaling is associated with a dramatic increase in apoptosis of WT megakaryocytes (MKs), but that overexpression of ERG blocks AKT-induced death. We further found that Gata1 mutations protect MKs from activated AKT-induced apoptosis. As a consequence, however, the enhanced signaling inhibits differentiation of Gata1 mutant, but not WT, MKs. Gata1 mutant cells that overexpress ERG with hyperactive AKT are characterized by diminished FOXO1/3a expression and an increased dependency on the c-Jun pathway similar to that seen in acute megakaryoblastic leukemia (AMKL) cell lines, acute myeloid leukemia (AML) with knockdown of FOXO3a, or AML with expression of myristoylated Akt. Additionally, we found that the AKT allosteric inhibitor MK2206 caused reduced cell viability and proliferation of AMKL cell lines. The contribution of aberrant AKT signaling during the ontogeny of Down syndrome-transient myeloproliferative disorder/AMKL indicates that AKT is a therapeutic target in this form of AML.

journal_name

Leukemia

journal_title

Leukemia

authors

Stankiewicz MJ,Crispino JD

doi

10.1038/leu.2013.33

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

1339-47

issue

6

eissn

0887-6924

issn

1476-5551

pii

leu201333

journal_volume

27

pub_type

杂志文章

相关文献

LEUKEMIA文献大全
  • Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells.

    abstract::On activation, umbilical cord blood (UCB) CD4(+) T cells demonstrate reduced expression of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), whereas maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4(+) T cells. Nuclear factor of activated T cel...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2008.234

    authors: Lesniewski ML,Haviernik P,Weitzel RP,Kadereit S,Kozik MM,Fanning LR,Yang YC,Hegerfeldt Y,Finney MR,Ratajczak MZ,Greco N,Paul P,Maciejewski J,Laughlin MJ

    更新日期:2008-12-01 00:00:00

  • Socioeconomic factors in the families of children with lymphoid malignancy in the UAE.

    abstract::Children of subcontinental (Indian and Pakistani) origin living in the United Arab Emirates (UAE) have previously been shown to have a higher relative frequency of ALL when compared to other ethnic groups. To analyze the possible effect of social class in this difference, a study of socioeconomic factors was conducted...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2400601

    authors: Révész T,Mpofu C,Oyejide C,Bener A

    更新日期:1997-04-01 00:00:00

  • Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse.

    abstract::In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment are lacking. Therefore, the value of flow MRD dete...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2014.186

    authors: Köhnke T,Sauter D,Ringel K,Hoster E,Laubender RP,Hubmann M,Bohlander SK,Kakadia PM,Schneider S,Dufour A,Sauerland MC,Berdel WE,Büchner T,Wörmann B,Braess J,Hiddemann W,Spiekermann K,Subklewe M

    更新日期:2015-02-01 00:00:00

  • Chloroquine induces basophilic differentiation of HL-60 cells.

    abstract::Many agents have been known to induce the differentiation of HL-60 cells. However, only a small number of reports on the basophilic differentiation of this cell line are known. In this study we show that the exposure of HL-60 cells to chloroquine induces to differentiate into basophils. This chloroquine-induced change...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Sasaki R,Furukawa Y,Okada K,Nakamura M,Yamane Y,Miura Y,Eguchi M

    更新日期:1997-04-01 00:00:00

  • Clinical significance of CD81 expression by clonal plasma cells in high-risk smoldering and symptomatic multiple myeloma patients.

    abstract::The presence of CD19 in myelomatous plasma cells (MM-PCs) correlates with adverse prognosis in multiple myeloma (MM). Although CD19 expression is upregulated by CD81, this marker has been poorly investigated and its prognostic value in MM remains unknown. We have analyzed CD81 expression by multiparameter flow cytomet...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2012.42

    authors: Paiva B,Gutiérrez NC,Chen X,Vídriales MB,Montalbán MÁ,Rosiñol L,Oriol A,Martínez-López J,Mateos MV,López-Corral L,Díaz-Rodríguez E,Pérez JJ,Fernández-Redondo E,de Arriba F,Palomera L,Bengoechea E,Terol MJ,de Paz R,Mar

    更新日期:2012-08-01 00:00:00

  • The human thrombopoietin gene is located on chromosome 3q26.33-q27, but is not transcriptionally activated in leukemia cells with 3q21 and 3q26 abnormalities (3q21q26 syndrome).

    abstract::We previously demonstrated that the EVI-1 gene was transcriptionally activated in the 3q21q26 syndrome and chromosomal breakpoints at 3q26 were clustered within 400 Kb of the EVI-1 gene. Since thrombocytosis is often observed in the 3q21q26 syndrome, we first mapped the thrombopoietin (TPO) gene and then we examined f...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Suzukawa K,Satoh H,Taniwaki M,Yokota J,Morishita K

    更新日期:1995-08-01 00:00:00

  • Impact of PTEN abnormalities on outcome in pediatric patients with T-cell acute lymphoblastic leukemia treated on the MRC UKALL2003 trial.

    abstract::PTEN gene inactivation by mutation or deletion is common in pediatric T-cell acute lymphoblastic leukemia (T-ALL), but the impact on outcome is unclear, particularly in patients with NOTCH1/FBXW7 mutations. We screened samples from 145 patients treated on the MRC UKALL2003 trial for PTEN mutations using heteroduplex a...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2015.206

    authors: Jenkinson S,Kirkwood AA,Goulden N,Vora A,Linch DC,Gale RE

    更新日期:2016-01-01 00:00:00

  • Altered transcription of the stem cell leukemia gene in myelofibrosis with myeloid metaplasia.

    abstract::An increased number of circulating CD34+ hematopoietic progenitors with a prominent proliferation of the megakaryocytic (MK) population are the hallmarks of the myeloproliferation in myelofibrosis with myeloid metaplasia (MMM). Analyzing the potential contribution of the stem cell leukemia (SCL) gene in MMM myeloproli...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2403089

    authors: Steunou V,Le Bousse-Kerdilès MC,Colin-Micouin A,Clay D,Chevillard S,Martyré MC,French INSERM Research Network on Myelofibrosis Myeloid Metaplasia.

    更新日期:2003-10-01 00:00:00

  • Is t(14;18)(q32;q21) a constant finding in follicular lymphoma? An interphase FISH study on 63 patients.

    abstract::The translocation (14;18)(q32;q21) is the hallmark of follicular lymphoma (FL). However, conventional cytogenetics and PCR techniques fail to detect it in at least 10% of cases. In order to evaluate the true incidence of this translocation in FL, we analyzed 63 patients with FL, and 17 patients with diffuse large cell...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402739

    authors: Godon A,Moreau A,Talmant P,Baranger-Papot L,Geneviève F,Milpied N,Zandecki M,Avet-Loiseau H

    更新日期:2003-01-01 00:00:00

  • Clonal diversity predicts adverse outcome in chronic lymphocytic leukemia.

    abstract::Genomic analyses of chronic lymphocytic leukemia (CLL) identified somatic mutations and associations of clonal diversity with adverse outcomes. Clonal evolution likely has therapeutic implications but its dynamic is less well studied. We studied clonal composition and prognostic value of seven recurrently mutated driv...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/s41375-018-0215-9

    authors: Leeksma AC,Taylor J,Wu B,Gardner JR,He J,Nahas M,Gonen M,Alemayehu WG,Te Raa D,Walther T,Hüllein J,Dietrich S,Claus R,de Boer F,de Heer K,Dubois J,Dampmann M,Dürig J,van Oers MHJ,Geisler CH,Eldering E,Levine RL

    更新日期:2019-02-01 00:00:00

  • Immunophenotypic features and configuration of immunoglobulin genes in hairy cell leukemia-Japanese variant.

    abstract::Immunophenotypes and Ig gene rearrangements were investigated in 12 patients with a variant form of hairy cell leukemia (HCL) termed HCL-Japanese variant (HCL-J), and in an HCL-J-derived cell line. The leukemic cells of HCL-J characteristically showed the phenotype of CD20+, CD5-, CD10-, CD11c+, CD22+, CD24- and CD25-...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Yamaguchi M,Machii T,Shibayama H,Tokumine Y,Hara J,Yutsudo M,Yamada O,Klobeck HG,Kitani T

    更新日期:1996-08-01 00:00:00

  • Monitoring of chimerism after allogeneic bone marrow transplantation with unmanipulated marrow by use of DNA polymorphisms.

    abstract::Highly polymorphic tandemly repetitive DNA sequences provide powerful genetic markers for the identification of individuals by restriction fragment length polymorphisms (RFLP) even in close relatives. Over a three-year period, 61 consecutive patients from a single institution undergoing allogeneic bone marrow transpla...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Suttorp M,Schmitz N,Dreger P,Schaub J,Löffler H

    更新日期:1993-05-01 00:00:00

  • Strong association of the HLA-DP6 supertype with childhood leukaemia is due to a single allele, DPB1*0601.

    abstract::We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering approximately 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes r...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2008.374

    authors: Taylor GM,Hussain A,Verhage V,Thompson PD,Fergusson WD,Watkins G,Lightfoot T,Harrison CJ,Birch JM,UKCCS Investigators.

    更新日期:2009-05-01 00:00:00

  • Deletion 5q in myelodysplastic syndrome: a paradigm for the study of hemizygous deletions in cancer.

    abstract::Hemizygous deletions are common molecular abnormalities in cancer. In some cases, these deletions highlight chromosomal loci containing tumor suppressor genes that undergo homozygous inactivation. In other cases, hemizygous deletions cause disease by allelic insufficiency for one or more genes. As the intact allele ha...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:10.1038/leu.2009.53

    authors: Ebert BL

    更新日期:2009-07-01 00:00:00

  • A phase I/II study of imatinib plus reinduction therapy for c-kit-positive relapsed/refractory acute myeloid leukemia: inhibition of Akt activation correlates with complete response.

    abstract::This phase I/II study evaluated imatinib as a c-kit inhibitor combined with mitoxantrone, etoposide and cytarabine therapy for patients with primary refractory or relapsed c-kit+ acute myeloid leukemia (AML). Imatinib was escalated through three dose levels in successive six patient cohorts. The combination was well t...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2011.34

    authors: Brandwein JM,Hedley DW,Chow S,Schimmer AD,Yee KW,Schuh AC,Gupta V,Xu W,Kamel-Reid S,Minden MD

    更新日期:2011-06-01 00:00:00

  • Role for c-jun N-terminal kinase in treatment-refractory acute myeloid leukemia (AML): signaling to multidrug-efflux and hyperproliferation.

    abstract::A relationship was proved between constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) and treatment failure in AML. Specifically, early treatment failure was predicted by the presence of constitutive JNK activity. The mechanistic origins of this association was sought. A multidrug resistant leukemic c...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402457

    authors: Cripe LD,Gelfanov VM,Smith EA,Spigel DR,Phillips CA,Gabig TG,Jung SH,Fyffe J,Hartman AD,Kneebone P,Mercola D,Burgess GS,Boswell HS

    更新日期:2002-05-01 00:00:00

  • JAK2V617F-mutant megakaryocytes contribute to hematopoietic stem/progenitor cell expansion in a model of murine myeloproliferation.

    abstract::The myeloproliferative neoplasms (MPNs) are characterized by hematopoietic stem/progenitor cell (HSPC) expansion and overproduction of mature blood cells. The JAK2V617F mutation is present in hematopoietic cells in a majority of patients with MPNs, but the mechanism(s) responsible for MPN stem cell expansion remain in...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2016.114

    authors: Zhan H,Ma Y,Lin CH,Kaushansky K

    更新日期:2016-12-01 00:00:00

  • Isolation and characterization of c-fos-expressing murine bone marrow stromal cell lines supporting myeloid differentiation.

    abstract::We have previously reported that constitutive expression of c-fos oncogene allows long-term proliferation of primary mouse bone marrow stromal cells favoring the granulocytic differentiation of myeloid precursors in an in vitro assay. Retrovirus-mediated gene transfer of the human c-fos gene was used here for immortal...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Steff AM,Bouaboula M,Mouchiroud G,Arnaud S,Roux P,Cassellas P,Piechaczyk M

    更新日期:1996-03-01 00:00:00

  • Reconstitution of peripheral blood lymphocyte subsets in the long-term disease-free survivors of patients with acute myeloblastic leukemia.

    abstract::The number of long-term survivors of patients with acute myeloblastic leukemia (AML) has increased as a result of the progress of chemotherapy. We examined the recovery of peripheral blood lymphocytes (PBL) subset after chemotherapy to clarify the reconstitution of the immune system in AML. Thirty patients with AML in...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2400891

    authors: Ohnishi K,Yamanishi H,Naito K,Utsumi M,Yokomaku S,Hirabayashi N,Ohno R

    更新日期:1998-01-01 00:00:00

  • L-type amino-acid transporter 1 (LAT1): a therapeutic target supporting growth and survival of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia.

    abstract::The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leuke...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/leu.2014.338

    authors: Rosilio C,Nebout M,Imbert V,Griessinger E,Neffati Z,Benadiba J,Hagenbeek T,Spits H,Reverso J,Ambrosetti D,Michiels JF,Bailly-Maitre B,Endou H,Wempe MF,Peyron JF

    更新日期:2015-06-01 00:00:00

  • Resistance of t(4;11) (MLL-AF4 fusion gene) leukemias to stress-induced cell death: possible mechanism for extensive extramedullary accumulation of cells and poor prognosis.

    abstract::Acute leukemias of the t(4;11) (MLL-AF4 fusion gene) type frequently have high white blood counts and extramedullary disease in multiple organs. In the present study we evaluated the hypotheses that this extensive disease is the result of extramedullary survival of leukemia cells due to resistance to stress-induced ce...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2401148

    authors: Kersey JH,Wang D,Oberto M

    更新日期:1998-10-01 00:00:00

  • Adult T cell leukemia cell lines that originated from primary leukemic clones also had a defect of expression of CD3-T cell receptor complex.

    abstract::Surface phenotypes and genotypes of six T cell lines established from four patients with adult T cell leukemia (ATL) were compared with those of fresh ATL cells. The surface antigen densities of CD3 and T cell receptor (TCR) complex examined by OKT3 and WT-31 mAbs on fresh ATL cells were low. But three IL-2-dependent ...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Shirono K,Hattori T,Matsuoka M,Matsushita S,Asou N,Takatsuki K

    更新日期:1988-11-01 00:00:00

  • Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia.

    abstract::Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-naï...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2403907

    authors: Motta M,Rassenti L,Shelvin BJ,Lerner S,Kipps TJ,Keating MJ,Wierda WG

    更新日期:2005-10-01 00:00:00

  • Expression of p16INK4A and p14ARF in hematological malignancies.

    abstract::The INK4A/ARF locus yields two tumor suppressors, p16INK4A and p14ARF, and is frequently deleted in human tumors. We studied their mRNA expressions in 41 hematopoietic cell lines and in 137 patients with hematological malignancies; we used a quantitative reverse transcription-PCR assay. Normal peripheral bloods, bone ...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2401557

    authors: Taniguchi T,Chikatsu N,Takahashi S,Fujita A,Uchimaru K,Asano S,Fujita T,Motokura T

    更新日期:1999-11-01 00:00:00

  • Do CLL B cells correspond to naive or memory B-lymphocytes? Evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells.

    abstract::Recent work suggests that chronic lymphocytic leukemia (B-CLL) expressing unmutated immunoglobulin V genes could correspond to the proliferation of naive B cells whereas those expressing mutated genes, may correspond to the proliferation of post-germinal center B cells. Current data from gene profiling expression have...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402731

    authors: Oppezzo P,Magnac C,Bianchi S,Vuillier F,Tiscornia A,Dumas G,Payelle-Brogard B,Ajchenbaum-Cymbalista F,Dighiero G,Pritsch O

    更新日期:2002-12-01 00:00:00

  • Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia.

    abstract::To determine the clinical relevance of in vitro drug chemoresistance in childhood acute myeloid leukemia, we used an MTT assay to test leukemic cells from 132 newly diagnosed children. Patients were diagnosed according to the French-American-British (FAB) classification as follows: M0 (n = 12), M1 (n = 16), M2 (n = 53...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402305

    authors: Yamada S,Hongo T,Okada S,Watanabe C,Fujii Y,Ohzeki T

    更新日期:2001-12-01 00:00:00

  • Assessment of minimal residual disease (MRD) in CBFbeta/MYH11-positive acute myeloid leukemias by qualitative and quantitative RT-PCR amplification of fusion transcripts.

    abstract::The inv(16)(p13q22) chromosomal rearrangement associated with FAB M4Eo acute myeloid leukemia (AML) subtype is characterized by the presence of the CBFbeta/MYH11 fusion transcript that can be used to detect minimal residual disease (MRD). However, qualitative RT-PCR studies of MRD have so far produced conflicting resu...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2402478

    authors: Guerrasio A,Pilatrino C,De Micheli D,Cilloni D,Serra A,Gottardi E,Parziale A,Marmont F,Diverio D,Divona M,Lo Coco F,Saglio G

    更新日期:2002-06-01 00:00:00

  • Homozygous deletions of the CDKN2 (MTS1/p16ink4) gene in cell lines established from children with acute lymphoblastic leukemia.

    abstract::Homozygous deletions of the CDKN2 (MTS1/p16ink4) gene have been found at high frequency in cell lines derived from a variety of adult solid tumors. In order to investigate the status of the CDKN2 gene in cell lines established from childhood acute lymphoblastic leukemia (ALL), we surveyed 25 lines representing the maj...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:

    authors: Zhou M,Gu L,James CD,He J,Yeager AM,Smith SD,Findley HW

    更新日期:1995-07-01 00:00:00

  • The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2m(null) mice.

    abstract::Hematopoietic stem cells are identified based on their functional ability to migrate via the blood circulation of transplanted recipients, to home to the host bone marrow and to durably repopulate this organ with high levels of maturing myeloid and lymphoid cells. While a small pool of undifferentiated stem cells with...

    journal_title:Leukemia

    pub_type: 杂志文章,评审

    doi:10.1038/sj.leu.2402684

    authors: Lapidot T,Kollet O

    更新日期:2002-10-01 00:00:00

  • Quality assurance in RT-PCR-based BCR/ABL diagnostics--results of an interlaboratory test and a standardization approach.

    abstract::Here we describe the results of an interlaboratory test for RT-PCR-based BCR/ABL analysis. The test was organized in two parts. The number of participating laboratories in the first and second part was 27 and 20, respectively. In the first part samples containing various concentrations of plasmids with the ela2, b2a2 ...

    journal_title:Leukemia

    pub_type: 杂志文章

    doi:10.1038/sj.leu.2401899

    authors: Burmeister T,Maurer J,Aivado M,Elmaagacli AH,Grünebach F,Held KR,Hess G,Hochhaus A,Höppner W,Lentes KU,Lübbert M,Schäfer KL,Schafhausen P,Schmidt CA,Schüler F,Seeger K,Seelig R,Thiede C,Viehmann S,Weber C,Wilhelm

    更新日期:2000-10-01 00:00:00